Complementary Roles of GCN5 and PCAF in Foxp3+T-Regulatory Cells
Complementary Roles of GCN5 and PCAF in Foxp3+T-Regulatory Cells
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DOI：
10.3390/cancers11040554
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发表时间：
2019-04-01
期刊：
影响因子：
5.2
通讯作者：
Hancock, Wayne W.
中科院分区：
文献类型：
--
作者：
Liu, Yujie;Bao, Chunrong;Hancock, Wayne W.
GCN5相关的N-乙酰转移酶(GNAT)家族的组蛋白/蛋白乙酰转移酶(HATS)在Foxp3+T调节(Treg)细胞中的功能尚不清楚，尽管这些酶在细胞生物学中具有普遍的重要性。我们现在发现两个典型的GNAT家族成员，GCN5(一般控制非抑制蛋白5，赖氨酸乙酰转移酶(KAT)2a)和p300/CBP相关因子(P300/CBP相关因子，Kat2b)通过部分不同和部分重叠的机制参与Treg功能。Gcn5或PCAF的缺失在体外并不影响Treg的发育或抑制功能，但确实影响了诱导性Treg(ITreg)的发育，并在体内消除了Treg依赖的同种异体移植物存活。在所有T细胞中，靶向每种HAT的效果截然不同；缺乏GCN5的小鼠显示同种异体移植存活时间延长，这表明这一HAT可能是同种移植受者表观遗传治疗的靶点，而缺乏PCAF的小鼠的移植发生了急性同种异体排斥反应。PCAF缺失也增强了免疫活性小鼠的抗肿瘤免疫。GCN5和PCAF的双重缺失导致Treg的稳定性和外周淋巴组织中Treg的数量下降，小鼠在出生后3-4周死于严重的自身免疫。这些数据表明，GNAT家族的HATS对Treg功能具有先前特征的Treg Hats(CBP、P300和Tip60)无法替代的贡献，可能是免疫肿瘤学中有用的靶点。
Functions of the GCN5-related N-acetyltransferase (GNAT) family of histone/protein acetyltransferases (HATs) in Foxp3+ T-regulatory (Treg) cells are unexplored, despite the general importance of these enzymes in cell biology. We now show that two prototypical GNAT family members, GCN5 (general control nonrepressed-protein 5, lysine acetyltransferase (KAT)2a) and p300/CBP-associated factor (p300/CBP-associated factor (PCAF), Kat2b) contribute to Treg functions through partially distinct and partially overlapping mechanisms. Deletion of Gcn5 or PCAF did not affect Treg development or suppressive function in vitro, but did affect inducible Treg (iTreg) development, and in vivo, abrogated Treg-dependent allograft survival. Contrasting effects were seen upon targeting of each HAT in all T cells; mice lacking GCN5 showed prolonged allograft survival, suggesting this HAT might be a target for epigenetic therapy in allograft recipients, whereas transplants in mice lacking PCAF underwent acute allograft rejection. PCAF deletion also enhanced anti-tumor immunity in immunocompetent mice. Dual deletion of GCN5 and PCAF led to decreased Treg stability and numbers in peripheral lymphoid tissues, and mice succumbed to severe autoimmunity by 3-4 weeks of life. These data indicate that HATs of the GNAT family have contributions to Treg function that cannot be replaced by the functions of previously characterized Treg HATs (CBP, p300, and Tip60), and may be useful targets in immuno-oncology.